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Amitriptilina para la fibromialgia en adultos

Appendices

Appendix 1. Methodological considerations for chronic pain

There have been several recent changes in how the efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with new criteria for what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with 'any improvement'. Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be of longer duration, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for the inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. To summarise some of the recent insights that must be considered in this new review:

  1. Pain results tend to have a U‐shaped distribution rather than a bell‐shaped distribution. This is true in acute pain (Moore 2011a; Moore 2011b), back pain (Moore 2010d), and arthritis (Moore 2010c), as well as in fibromyalgia (Straube 2010); in all cases average results usually describe the experience of almost no‐one in the trial. Data expressed as averages are potentially misleading, unless they can be proven to be suitable.

  2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials of less than 12 weeks duration, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2010c); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic‐type pain.

  3. The proportion of patients with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis to 30% in fibromyalgia (Moore 2009; Moore 2010c; Moore 2013b; Moore 2014b; Straube 2010; Sultan 2008). A Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.

  4. Individual patient analyses indicate that patients who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (Moore 2010b; Moore 2014a).

  5. Imputation methods such as last observation carried forward (LOCF), used when participants withdraw from clinical trials, can overstate drug efficacy especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012b).

Appendix 2. MEDLINE (via OVID) search strategy

  1. exp PAIN/

  2. exp PERIPHERAL NERVOUS SYSTEM DISEASES/

  3. exp SOMATOSENSORY DISORDERS/

  4. FIBROMYALGIA/ or exp MYOFASCIAL PAIN SYNDROMES/ or POLYMYALGIA RHEUMATICA/

  5. ((pain* or discomfort*) adj10 (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)).mp.

  6. (fibromyalgi* or fibrosti* or FM or FMS).mp.

  7. ((neur* or nerv*) adj6 (compress* or damag*)).mp.

  8. 1 or 2 or 3 or 4 or 5 or 6 or 7

  9. Amitriptyline/

  10. (am?tr?pt?lin* or amitriptyliini).mp.

  11. 9 or 10

  12. 8 and 11

  13. randomized controlled trial.pt.

  14. controlled clinical trial.pt.

  15. randomized.ab.

  16. placebo.ab.

  17. drug therapy.fs.

  18. randomly.ab.

  19. trial.ab.

  20. groups.ab.

  21. or/13‐20

  22. exp animals/ not humans.sh.

  23. 21 not 22

  24. 23 and 12

Appendix 3. EMBASE (via OVID) search strategy

  1. exp chronic pain/

  2. exp peripheral neuropathy/

  3. exp somatosensory disorder/

  4. fibromyalgia/ or exp myofascial pain/ or rheumatic polymyalgia/

  5. ((pain* or discomfort*) adj10 (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)).mp.

  6. (fibromyalgi* or fibrosti* or FM or FMS).mp.

  7. ((neur* or nerv*) adj6 (compress* or damag*)).mp.

  8. 1 or 2 or 3 or 4 or 5 or 6 or 7

  9. amitriptyline/

  10. (am?tr?pt?lin* or amitriptyliini or Tryptomer or Elavil or Tryptizol or Laroxyl or Sarotex or Lentizol or Endep).mp.

  11. 9 or 10

  12. 8 and 11

  13. random*.ti,ab.

  14. factorial*.ti,ab.

  15. (crossover* or cross over* or cross‐over*).ti,ab.

  16. placebo*.ti,ab.

  17. (doubl* adj blind*).ti,ab.

  18. assign*.ti,ab.

  19. allocat*.ti,ab.

  20. RANDOMIZED CONTROLLED TRIAL.sh.

  21. DOUBLE‐BLIND PROCEDURE.sh.

  22. CROSSOVER PROCEDURE.sh.

  23. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22

  24. 12 and 23

Appendix 4. CENTRAL search strategy

  1. MeSH descriptor Pain explode all trees

  2. MeSH descriptor Peripheral Nervous System Diseases explode all trees

  3. MeSH descriptor Somatosensory Disorders explode all trees

  4. MeSH descriptor Fibromyalgia, this term only

  5. MeSH descriptor Myofascial Pain Syndromes explode all trees

  6. MeSH descriptor Polymyalgia Rheumatica explode all trees

  7. ((pain* or discomfort*) and (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)):ti,ab,kw

  8. (fibromyalgi* or fibrosti* or FM or FMS):ti,ab,kw

  9. ((neur* or nerv*) and (compress* or damag*)):ti,ab,kw

  10. (1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9)

  11. MeSH descriptor Amitriptyline

  12. (am?tr?pt?lin* or amitriptyliini or Tryptomer or Elavil or Tryptizol or Laroxyl or Sarotex or Lentizol or Endep).ti,ab,kw

  13. 11 or 12

  14. 10 and 13

  15. Limit 14 to CENTRAL

Appendix 5. Summary of outcomes in individual studies: efficacy

Study

Treatment

(taken at night, unless stated)

Pain outcome

Other efficacy outcome

Braz 2013

Amitriptyline 25 mg = 13
P. ginseng extract = 12
Placebo = 13

VAS PI reduced in all groups compared with baseline, but no statistically significant difference between groups

No significant differences between groups on any of the measures: fatigue, sleep, QoL

Carette 1986

Amitriptyline 50 mg = 27
Placebo = 32

Dose titration:
Week 1 ‐ 10 mg/d
Weeks 2 to 4 ‐ 25 mg/d
Weeks 5 to 9 ‐ 50 mg/d

Global impression of change ‐ moderate or marked at 9 weeks
Amitriptyline = 17/27

Placebo = 10/32
Global impression of change ‐ marked
Amitriptyline = 6/27

Placebo = 5/32

No difference in tender points, but improved sleep with amitriptyline

Carette 1994

Amitriptyline 25 mg = 84
Cyclobenzaprine 30 mg = 82
Placebo = 42

Dose titration:
Amitriptyline week 1 ‐ 10 mg/d
Weeks 2 to 12 ‐ 25 mg/d
Weeks 13 to 24 ‐ 50 mg/d
Cyclobenzaprine week 1 ‐ 10 mg/d
Weeks 2 to 12 ‐ 20 mg/d
Weeks 13 to 24 ‐ 30 mg/d

Significant improvers (50% improvement in pain, sleep, fatigue, global, myalgic score, 4 of 6):
Amitriptyline = 30/84
Cyclobenzaprine = 27/82

Placebo = 8/42

No difference for change in mean pain score (from graph):
Amitriptyline dropped 67 to 48 mm

Placebo dropped 69 to 54 mm

No significant end of trial difference for sleep, fatigue, global, tender points

Carette 1995

Amitriptyline 25 mg = 22

Placebo = 20

Cross‐over

Significant improvers (50% improvement in pain, sleep, fatigue, global, myalgic score, 4 of 6)

Amitriptyline = 6/22

Placebo = 0/22

VAS pain at 8 weeks (mean ± SD)

Amitriptyline = 5.1 ± 3.2
Placebo = 7.1 ± 2.1

Significant difference for sleep, patient global, fatigue, but not tender points

de Zanette 2014

Amitriptyline 25 mg daily = 21

Melatonin 10 mg daily = 21

Amitriptyline 25 mg + melatonin 10 mg daily = 21

Mean PI in last 24 h during last week of treatment (100 mm VAS) vs before treatment
Amitriptyline 63 to 50 = 13
Melatonin 65 to 48 = 17
Amitriptyline + melatonin 69 to 49 = 20

No significant difference observed between groups in the numbers of analgesic used in last week of treatment, sleep quality and number of tender points

Ginsberg 1996

Amitriptyline 25 mg = 24

Placebo = 22

Responder (at least 50% improvement pain and or global) at 8 weeks:
Amitriptyline = 14/ 24

Placebo = 0/22

VAS pain (mean ± SD)

Amitriptyline baseline 3.8 ± 2.4
Amitriptyline end 7.0 ± 1.3
Placebo baseline 7.0 ± 1.4
Placebo end 5.0 ± 2.1

Major changes in patient global, tender point count and score, sleep, fatigue, and stiffness

Goldenberg 1986

Balanced assignment quoted, but actual numbers in each group not given Therefore we assume:
Amitriptyline 25 mg = 16

Placebo = 16

(Also included naproxen 2 x 500 mg and amitriptyline + naproxen treatment arms)

VAS pain at 6 weeks (mean, from graph):
Amitriptyline = 5.4

Placebo = about 7.4

Significant difference only at 4 weeks, not at 6 weeks. No dispersion given

End of trial ‐ significant benefit for amitriptyline versus placebo for fatigue, sleep, and patient global assessment, but not tender points

Goldenberg 1996

Amitriptyline 25 mg = 21
Fluoxetine 20 mg = 22
Amitriptyline + Fluoxetine = 19

Placebo = 19

Cross‐over

VAS pain at 6 weeks (mean ± SD)
Amitriptyline = 64 ± 28
Fluoxetine = 58 ± 26
Amitriptyline + Fluoxetine = 43 ± 29

Placebo = 82 ± 17

Apparent significant results, probably amitriptyline versus placebo, for pain, FIQ, sleep, and global, but not fatigue or tender points
Generally effect amitriptyline + fluoxetine > fluoxetine ≥ amitriptyline > placebo

% change before/after calculated for each patient gave similar pattern to group means ‐ numbers given for > 25% improvement in FIQ only:
Amitriptyline = 5/21, Fluoxetine = 7/22, Amitriptyline + Fluoxetine = 12/19, Placebo = 1/19

Hannonen 1998

Amitriptyline 25 mg = 42
Moclobemide 450 mg (am and pm) = 43

Placebo = 45

Titration to max 37.5 mg A, 600 mg M

VAS (mean ± SD)
Amitriptyline baseline 6.0 ± 2.1
Amitriptyline end 4.5 ± 2.8
Moclobemide baseline 5.7 ± 2.1
Moclobemide end 4.5 ± 2.7

Placebo baseline 5.7 ± 2.3
Placebo end 5.2 ± 2.7
Number of responders not given, but some response in 74% (amitriptyline) versus 49% (placebo), 54% (moclobemide)

General health, sleep fatigue tender points, and clinician severity all improved with amitriptyline and placebo, but no obvious between group difference, except perhaps sleep

AE: adverse effect; d: day; FIQ: Fibromyalgia Impact Questionnaire; QoL: quality of life; SD: standard deviation; VAS: visual analogue scale

Appendix 6. Summary of outcomes in individual studies: adverse events and withdrawals

Study

Treatment

(taken at night, unless stated)

Adverse events

Withdrawals

Braz 2013

Amitriptyline 25 mg = 13
P. ginseng extract = 12
Placebo = 13

Not reported

All cause:
Amitriptyline 3/13
P. ginseng 4/12
Placebo 7/13
AE:
Amitriptyline 2/13
P. ginseng 3/12
Placebo 3/13

No specific LoE withdrawals

Carette 1986

Amitriptyline 50 mg = 27
Placebo = 32

Dose titration:
Week 1 ‐ 10 mg/d
Weeks 2 to 4 ‐ 25 mg/d
Weeks 5 to 9 ‐ 50 mg/d

Patients with ≥ 1 AE:
Amitriptyline = 19/27

Placebo = 4/32

"minor side effects" ‐ mostly drowsiness and xerostomia

Total:
Amitriptyline = 7/27, Placebo = 4/32
LoE:
Amitriptyline = 1/27 Placebo = 0/32
AE:
Amitriptyline = 2/27 Placebo = 2/32
Other:
Amitriptyline = 4/27 Placebo = 2/32

Carette 1994

Amitriptyline 25 mg = 84
Cyclobenzaprine 30 mg = 82
Placebo = 42

Dose titration:
Amitriptyline week 1 ‐ 10 mg/d
Weeks 2 to 12 ‐ 25 mg/d
Weeks 13 to 24 ‐ 50 mg/d
Cyclobenzaprine week 1 ‐ 10 mg/d
Weeks 2 to 12 ‐ 20 mg/d
Weeks 13 to 24 ‐ 30 mg/d

Patients with ≥ 1 AE:

Amitriptyline = 80/84
Cyclobenzaprine = 80/82

Placebo = 26/42

Most common ‐ dry mouth, somnolence, dizziness, weight gain

Total:

Amitriptyline = 14/84, Cyclobenzaprine = 24/82, Placebo = 14/42
LoE:
Amitriptyline = 5/84, Cyclobenzaprine = 6/82, Placebo = 7/42
AE:
Amitriptyline = 5/84, Cyclobenzaprine = 11/82, Placebo = 2/42
Other:
Amitriptyline = 4/84, Cyclobenzaprine = 7/82, Placebo = 5/42

Carette 1995

Amitriptyline 25 mg = 22

Placebo = 20

Cross‐over

Not reported

2 withdrawals after first period A (not drug‐related)

de Zanette 2014

Amitriptyline 25 mg daily = 21

Melatonin 10 mg daily = 21

Amitriptyline 25 mg + melatonin 10 mg daily = 21

Minor
Amitriptyline 8/21 (nausea, dizziness, weight gain, dry mouth, headache)
Melatonin 5/21 (no details)

Amitriptyline + melatonin not reported

Major
Amitriptyline 5/21 (dizziness, nightmares, drowsiness, headache, behavioural change, worsening pain)
Melatonin 6/21 (no details)

Amitriptyline + melatonin not reported

AE:

Amitriptyline 2/21
Melatonin 2/21
Amitriptyline + melatonin 2/21

No other withdrawals reported

Ginsberg 1996

Amitriptyline 25 mg = 24

Placebo = 22

Amitriptyline = 7/24 (3 dry mouth, 2 digestive symptoms, 1 vertigo, 2 neuro‐psychic symptoms)

Placebo = 0/22

1 in amitriptyline due to AE

Goldenberg 1986

Balanced assignment quoted, but actual numbers in each group not given. Therefore we assume:
Amitriptyline 25 mg = 16

Placebo = 16

(Also included naproxen 2 x 500 mg, and amitriptyline + naproxen treatment arms)

8 patients (across groups) complained of side effects but did not discontinue medication (dry mouth, dyspepsia, diarrhoea)

Amitriptyline = 1 (lost to follow‐up)
N = 1 (lost to follow‐up)
Amitriptyline + naproxen = 1 (AE ‐ somnolence)

Placebo = 1 (AE ‐ epigastric distress)

Goldenberg 1996

Amitriptyline 25 mg = 21
Fluoxetine 20 mg = 22
Amitriptyline + Fluoxetine = 19

Placebo = 19

Cross‐over

Not reported

12/31 did not complete
Amitriptyline = 1 (other)
Fluoxetine = 4 (1 AE, 3 LoE)
Amitriptyline + Fluoxetine = 5 (3 AE, 2 other)

Placebo = 1 (AE)

Washout after Amitriptyline + Fluoxetine = 1 (LoE)

Hannonen 1998

Amitriptyline 25 mg = 42
Moclobemide 450 mg (am and pm) = 43

Placebo = 45

Titration to max 37.5 mg amitriptyline, 600 mg moclobemide

Patients with ≥ 1 AE:
Amitriptyline = 31/42 (dry mouth, fatigue)
Moclobemide = 33/43 (headache, difficulty falling asleep)

Placebo = 36/45 (fatigue, headache)

Withdrawals:
Amitriptyline = 10/42 (2 LoE, 5 AE, 3 other)
Moclobemide = 13/43 (4 LoE, 6 AE, 3 other)

Placebo = 15/45 (7 LoE, 5 AE, 3 other)

AE: adverse effect; LoE: lack of efficacy; SAE: serious adverse effect

Flow diagram.
Figures and Tables -
Figure 1

Flow diagram.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Amitriptyline versus placebo, outcome: 1.1 Third‐tier efficacy.
Figures and Tables -
Figure 4

Forest plot of comparison: 1 Amitriptyline versus placebo, outcome: 1.1 Third‐tier efficacy.

Third‐tier evidence: substantial pain relief
Figures and Tables -
Figure 5

Third‐tier evidence: substantial pain relief

Comparison 1 Amitriptyline versus placebo, Outcome 1 Third‐tier efficacy.
Figures and Tables -
Analysis 1.1

Comparison 1 Amitriptyline versus placebo, Outcome 1 Third‐tier efficacy.

Comparison 1 Amitriptyline versus placebo, Outcome 2 At least 1 adverse event.
Figures and Tables -
Analysis 1.2

Comparison 1 Amitriptyline versus placebo, Outcome 2 At least 1 adverse event.

Comparison 1 Amitriptyline versus placebo, Outcome 3 All‐cause withdrawal.
Figures and Tables -
Analysis 1.3

Comparison 1 Amitriptyline versus placebo, Outcome 3 All‐cause withdrawal.

Comparison 1 Amitriptyline versus placebo, Outcome 4 Adverse event withdrawal.
Figures and Tables -
Analysis 1.4

Comparison 1 Amitriptyline versus placebo, Outcome 4 Adverse event withdrawal.

Comparison 1 Amitriptyline versus placebo, Outcome 5 Lack of efficacy withdrawal.
Figures and Tables -
Analysis 1.5

Comparison 1 Amitriptyline versus placebo, Outcome 5 Lack of efficacy withdrawal.

Amitriptyline compared with placebo for fibromyalgia

Patient or population: adults with fibromyalgia

Settings: community

Intervention: amitriptyline 25 to 50 mg daily

Comparison: placebo

Outcomes

Probable outcome with intervention

Probable outcome with placebo

NNT or NNH and/or relative effect (95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

At least 50% reduction in pain or equivalent (substantial)

360 in 1000

110 in 1000

RR 2.9 (1.7 to 4.9)

NNT 4.1 (2.9 to 6.7)

4 studies, 275 participants

Very low

Small number of studies and participants

At least 30% reduction in pain or equivalent (moderate)

no data

Adverse event withdrawals

80 in 1000

90 in 1000

RR 1.03 (0.49 to 2.2)

NNTp not calculated

4 studies, 298 participants

Very low

Small number of studies and participants

Serious adverse events

none reported

Death

none reported

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Figures and Tables -
Comparison 1. Amitriptyline versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Third‐tier efficacy Show forest plot

4

275

Risk Ratio (M‐H, Fixed, 95% CI)

2.88 [1.69, 4.91]

1.1 Fibromyalgia

4

275

Risk Ratio (M‐H, Fixed, 95% CI)

2.88 [1.69, 4.91]

2 At least 1 adverse event Show forest plot

4

318

Risk Ratio (M‐H, Fixed, 95% CI)

1.54 [1.29, 1.84]

3 All‐cause withdrawal Show forest plot

7

418

Risk Ratio (M‐H, Fixed, 95% CI)

0.77 [0.53, 1.11]

4 Adverse event withdrawal Show forest plot

4

298

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.49, 2.16]

5 Lack of efficacy withdrawal Show forest plot

3

272

Risk Ratio (M‐H, Fixed, 95% CI)

0.42 [0.19, 0.95]

Figures and Tables -
Comparison 1. Amitriptyline versus placebo